8EBM

Structure of KLHDC2 substrate binding domain bound to KLHDC2's C-degron mimic

Summary for 8EBM

• Entry DOI: 10.2210/pdb8ebm/pdb
• Descriptor: Kelch domain-containing protein 2, ASN-GLN-ARG-PHE-GLY-SER-ASN-ASN-THR-SER-GLY-SER (3 entities in total)
• Functional Keywords: e3 ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 82067.37

Authors

Scott, D.C.,Schulman, B.A. (deposition date: 2022-08-31, release date: 2023-02-22, Last modification date: 2023-10-25)

Primary citation

Scott, D.C.,King, M.T.,Baek, K.,Gee, C.T.,Kalathur, R.,Li, J.,Purser, N.,Nourse, A.,Chai, S.C.,Vaithiyalingam, S.,Chen, T.,Lee, R.E.,Elledge, S.J.,Kleiger, G.,Schulman, B.A.
E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
Mol.Cell, 83:770-786.e9, 2023

PubMed Abstract: E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins with terminal degron-like sequences remains unclear. Here, we report that human KLHDC2, a CRL2 substrate receptor targeting C-terminal Gly-Gly degrons, is regulated through interconversion between two assemblies. In the self-inactivated homotetramer, KLHDC2's C-terminal Gly-Ser motif mimics a degron and engages the substrate-binding domain of another protomer. True substrates capture the monomeric CRL2, driving E3 activation by neddylation and subsequent substrate ubiquitylation. Non-substrates such as NEDD8 bind KLHDC2 with high affinity, but its slow on rate prevents productive association with CRL2. Without substrate, neddylated CRL2 assemblies are deactivated via distinct mechanisms: the monomer by deneddylation and the tetramer by auto-ubiquitylation. Thus, substrate specificity is amplified by KLHDC2 self-assembly acting like a molecular timer, where only bona fide substrates may bind before E3 ligase inactivation.

PubMed: 36805027
DOI: 10.1016/j.molcel.2023.01.019

Experimental method

X-RAY DIFFRACTION (1.58 Å)